The proposed application is part of a comprehensive research effort to molecularly define human genes that are implicated in severe nearsightedness, or myopia. Myopia occurs when the focused image falls anterior to the retinal photoreceptor layer of the eye. Myopia is the most common human eye disease, and severe cases may lead to blinding disorders such as premature cataracts, glaucoma, retinal detachment, and macular degeneration. Myopia is an enormous public health problem, and has been cited as the 4th leading cause of blindness in the United States. While there are genetic syndromes with myopia as a clinical feature, myopia does occur in an inherited fashion as an isolated condition. There is substantial evidence that genetic factors play a significant role in the development of non-syndromic high myopia. Our laboratory has mapped three autosomal dominant high myopia loci (MYP2- chromosome 18p11.31, MYP3 - chromosome 12q23.1-q24, and a locus at chromosome 17q21-q22), and refined the X-linked high myopia locus (MYP1 at chromosome Xq28). The Specific Aims of this proposal are to: 1) identify and recruit families with high myopia to map and refine existing myopia loci; and 2) identify the MYP2 gene using a positional candidate gene screening approach. Identification of the MYP2 gene will help define the genetic basis of classic high myopia, and may provide insight into the molecular basis of myopia. The determination of myopia gene mutations will contribute to our understanding of eye growth and development, as well as provide a framework for examining the genetic etiology of other refractive disorders. Identifying the implicated genes for myopia susceptibility will provide a fundamental molecular understanding of how myopia occurs, and may lead to directed physiologic (i.e. pharmacologic, gene therapy) interventions. This effort will contribute to our long-term goal to devise diagnostic and therapeutic strategies for the severe forms of this potentially blinding eye disease, which presently has no effective treatment.